The long term objective of the research described in this proposal tests the hypothesis that different prolactin (PRL) cells within the individual rat pituitary gland secrete PRL molecules that have different body targets, including those of the immune system. It also tests the ideas that differential activities of these PRL molecules depend upon 1) the estrogen status of the animal; 2) native cell to cell contacts in the pituitary; as well as 3) the location of the PRL cell within the pituitary gland. The research relies on a rapidly accumulating data base which shows that PRL specifically controls activation of splenic lymphocytes from the ovariectomized rat in terms of its ability to 1) induce interleukin 2 (IL-2) membrane receptors; 2) produce IL-2 molecules; and 3) cause cell division in T lymphocytes from the host spleen and thymus. These PRL-mediated events occur only in splenocyte from the female rat, and only when the estrogen levels of the host are relatively low (diestrous). They do not occur in splenocyte from females at estrous or in males; thus making a strong case for a physiological role of PRL in immunity. The first specific aim of the research investigates different cellular and molecular mechanisms within the individual rat pituitary gland that are likely to be involved in the control of release of PRL molecules which eventually target immune cells. The second aim tests the activities of the secreted PRL's directly on various cells of the host's immune system. The third aim tests the idea that lymphokines released from RL-stimulated lymphocytes act directly on pituitary cells by a feedback loop to regulate PRL secretion. The geographic location of the PRL cell within the rat pituitary is key to this research. The project is clinically relevant since 50% of all human breast cancers occur in the upper left quadrant of the breast and since human pituitary microadenomas which produce PRL usually are localized to the lateral wings of the pituitary gland. In this respect the female rat serves as an excellent model for probing new mechanisms responsible for these human diseases.